Tolerance mechanisms for autoreactive T cells can be of “intrinsic” and “extrinsic” varieties. Intrinsic mechanisms include deletion and anergy of self-reactive T cells, while extrinsic mechanisms include different regulatory T cells (Tregs) that suppress other self-reactive T cells. One type of extrinsic suppressor is the CD25+ CD4+ T cell, which constitutes 5-10% of CD4+ peripheral T cells. These are produced in the thymus and maintain tolerance to self-antigens, as well as play a role in other immune responses, such as in infection, transplants and graft versus host disease. In autoimmune diseases such as diabetes, considerable effort has been focused on expanding the small numbers of such Tregs. Expansion of this population using methods such as, for example, employing dendritic cells presenting antigenic peptide or a T cell receptor cross-linking agent, are described in U.S. patent application Ser. No. 11/074,925, filed Mar. 9, 2005.
However, the CD25− CD4+ T cell population is a more abundant population with the potential to differentiate into Tregs. While it is known that this T cell population can be differentiated into CD4+CD25+ T regs by stimulation with mitogenic antibodies in the presence of TGF-β1, it is not known whether these induced cells are functionally identical to Tregs that develop in the thymus. Such “induced T regs” with islet specificity can prevent diabetes in lymphopoietic models, but their ability to induce tolerance at late pathogenic stages of autoimmunity, such as in already-diabetic NOD mice, has not been fully addressed.
In T cell population, the transcription factor, FoxP3, is important for CD25+ CD4+ T cell suppressor activity, and children who are born with defective FoxP3 rapidly develop autoimmunity, such as, for example, autoimmune diabetes. Models for the study of autoimmunity have played a critical role in both the understanding of the pathogenesis, and the devising of therapeutic strategies for these diseases. In a mouse model of autoimmune diabetes, the non-obese diabetic (NOD) mice, for example, CD25+ CD4+ regulatory T cells inhibit diabetes development, making this extrinsic tolerance mechanism an attractive target to develop antigen-specific therapies for autoimmune disease. In an experimental model of multiple sclerosis mediated by transgenic T cells specific to myelin basic protein, CD25+ CD4+ T cells specific for this antigen showed better suppression of disease than CD25+ CD4+ T cells with T cell receptors (TCRs) specific for other antigens. These findings suggest a role for antigen-specific CD25+ CD4+ T cells in suppressing autoimmunity.
Means for expanding CD25+ CD4+ T cells without the use of mitogenic stimuli to differentiate T regs has numerous potential therapeutic advantages.